A relationship between diminished sleep qualities, decreased cognitive function and increased risk of certain neurodetenerative disorders, such as Alzheimer disease has been recently identified. The association between sleep quality and Alzheimer disease has been found to be bidirectional, i.e., sleep disturbances are a comorbidity of Alzheimer disease and decreases in sleep quality are associated with an increase in severity of Alzheimer disease pathology. In the specific case of Alzheimer disease soluble β-amyloid is measurable in cerebrospinal fluid (“CSF”) and interstitial fluid, with the level of soluble β-amyloid correlating with the extent of plaque deposition of insoluble β-amyloid in the brain. Brown, B. M., et al., The Relationship between Sleep Quality and Brain Amyloid Burden, SLEEP 39(5), 2016, p. 1063. Brown, et al. specifically found a correlation between sleep latency (the time to fall asleep) and β-amyloid burden in its study, but were careful to contrast their results with other studies that found an absence of such correlation.
Recently, researchers identified the glymphatic system, a system managed by the brain's glial cells that expand and contract to control the flow of CSF and clearing of soluble β-amyloid present in the CSF. During deep sleep, particularly stage 3, non-REM, slow wave sleep, the glymphatic system is activated to allow the brain to rid itself of β-amyloid and other waste products, including proteins such as tau protein and α-synuclean, peptides, lactate or ammonia that are the product of neuronal metabolism and present in the interstitial fluid around the brain cells. Nedergaard, M., Sleep Drives Metabolic Clearance from the Adult Brain, (Science Vol 342, Oct. 18, 2013, p. 373-377.
Astrocytes, star-shaped glial cells, express aquaporin 4 water channel (AQP4). Penetrating arteries which end in the brain are covered by astrocytic end feet which express AQP4. This perivascular space around the arteries is a mechanism that permits rapid influx observable with tracer. CSF first passes from the pariarterial space, through the aquaporin 4 (AQP4) water channels, into the interstitial space, where waste products are driven by convective flux toward the veins. The CSF exchanges with interstitial fluid containing waste products (such as, for example, β-amyloid, tau, α-synuclean, etc.), the interstitial fluid then enters the paravenous space, eventually reaching lymphatic vessels in the neck, and later the systemic circulation, where the proteins travel to the liver, where they are metabolized.
In this way the brain eliminates waste products of neuronal metabolism during n3, non-REM, slow wave sleep by expanding the interstitial fluid volume which effectively washes away the waste products in the interstitial fluid. Failure to remove these waste products, including β-amyloid and tau proteins implicated in Alzheimer disease and α-synuclean implicated in Parkinson's disease.
In healthy adults, sleep typically begins with NREM sleep. The pattern of clear rhythmic alpha activity associated with wakefulness gives way to N1, the first stage of sleep, which is defined by a low-voltage, mixed-frequency pattern. The transition from wakefulness to N1 occurs seconds to minutes after the start of the slow eye movements seen when a person first begins to nod off. This first period of N1 typically lasts just one to seven minutes. The second stage, or N2, which is signaled by sleep spindles and/or K complexes in the EEG recording, comes next and generally lasts 10 to 25 minutes. As N2 sleep progresses, there is a gradual appearance of the high-voltage, slow-wave activity characteristic of N3, the third stage of NREM sleep. This stage, which generally lasts 20 to 40 minutes, is referred to as “slow-wave,” “delta,” or “deep” sleep. As NREM sleep progresses, the brain becomes less responsive to external stimuli, and it becomes increasingly difficult to awaken an individual from sleep.
Following the N3 stage of sleep, a series of body movements usually signals an “ascent” to lighter NREM sleep stages. Typically, a 5- to 10-minute period of N2 precedes the initial REM sleep episode. REM sleep comprises about 20 to 25 percent of total sleep in typical healthy adults. NREM sleep and REM sleep continue to alternate through the night in a cyclical fashion. Most slow-wave NREM sleep occurs in the first part of the night; REM sleep episodes, the first of which may last only one to five minutes, generally become longer through the night. During a typical night, N3 sleep occupies less time in the second cycle than the first and may disappear altogether from later cycles. The average length of the first NREM-REM sleep cycle is between 70 and 100 minutes; the average length of the second and later cycles is about 90 to 120 minutes.
The hypothalamus is anatomically positioned adjacent the third ventricle of the brain. Without intending to be bound to theory, it is believed, that by signaling the hypothalamus to activate sleep, and in particular n3 stage non-REM sleep, the glymphatic system is then regulated to increase CSF flux throughout the brain ventricles, with the resulting effect of increasing the glymphatic clearing of potentially deleterious proteins and other molecules present in the CSF and interstitial fluid. Assuming this to be the case, it is theorized by the present inventors that administration of a composition capable of substantially avoiding first pass metabolism, crossing the blood-brain barrier, and acting on the hypothalamus to stimulate sleep, and in particular n3 stage non-REM sleep, has the effect of increasing glymphatic activity and, therefore, clearing the metabolic waste products of neuronal metabolism from the brain and not allowing them to accumulate and form deleterious plaques implicated in various neuro-degenerative disorders.
Vitamins, minerals, amino acids, and co-enzymes are compounds required by an animal, mammalian or human body in small amounts for metabolism, biophysiological repair, to protect health, and for proper growth and cellular reproduction. These compounds also assist in the formation of hormones, blood cells, nervous-system chemicals, and genetic material. Vitamins, minerals, amino acids, and co-enzymes are often referred to as nutrients, defined herein as a substance or ingredient which may be found in food which imparts a medicinal or health benefit. The various nutrient compounds are not chemically related, and most differ in their physiological actions. They generally act as catalysts, combining with proteins to create metabolically active enzymes that in turn produce hundreds (or more) of important chemical reactions throughout the body. Without nutrients, many of these reactions would slow down or cease. The intricate ways in which nutrients act on the body (e.g., positive and negative feedback regulatory processes), however, are still far from clear.
Dietary supplements are generally nutrient mixtures commonly taken in single mega-dose dosage forms which contain vitamin, mineral and other nutrient doses. Although mega-dose regimens are a common practice for the prevention of disease, there is a great deal of debate in the conventional literature regarding the efficacy of such regimens. Moreover, consuming large doses of vitamins, minerals, or other nutrients, in the absence of some deficiency or without proper medical supervision, may cause harmful toxic effects and/or result in hypervitaminosis.
Additionally, a consumer usually has little choice in choosing the variety of ingredients, dosage levels, or dosing regimens of a conventional dietary supplement, such as a standard vitamin tablet. Conventional dietary supplements may be effective for a general purpose, but can provide an excess of vitamins, minerals, stimulants, or other compounds which a consumer does not desire, or those supplements may not adequately target an individual's specific dietary need or desired biological response. Additionally, conventional dosage forms of dietary supplements only allow a consumer to take one or two doses per 24 hour period. As a result, conventional dietary supplements fail to recognize that the physiological state and resultant nutrient requirements of any single individual can depend upon and fluctuate based upon a number of different biophysical variables during the course of each day or dosing regimen. For example, individual variations in diet, and the amount and intensity of physical activity, provide physical and chemical stimuli that stress various systems of the body to differing degrees from one person to the next and for each of those individuals on any given day. Thus, standard “one size fits all” mega-dose dosage forms/regimens are not amenable to empirical dosage adjustment to achieve an individualized biophysiological objective or response such as, but not limited to, enhanced sleep quality, initiation of sleep, sleep maintenance, and the like.
Another drawback with most conventional dietary supplements is that they suffer from poor degrees and/or rates at which the various nutrients are absorbed into the systemic circulation of the body and made available for biophysiological activity (e.g., “bioavailability”). These degrees or rates of bioavailability typically depend upon the dose, dosage form, and method of administration.
One particular barrier to efficient nutrient bioavailability is “first-pass metabolism” or, synonymously “first-pass effect.” First-pass metabolism is generally understood by those in the field of pharmacology to mean the intestinal and/or hepatic degradation or alteration of a substance taken by mouth, which after absorption, removes some of the active substance from the blood before it enters the general circulation and is available to the body. Alternatively, first-pass metabolism is understood to mean a process in which the nutrient compound(s) are modified, activated, or inactivated before they enter the systemic circulation, or are left unchanged and excreted.
For example, it is generally understood by those skilled in at least the nutraceutical and/or supplements field that one significant drawback to “mega-dosing” of vitamins and minerals is that increased dosages may not be adequately absorbed into the body, or may actually decrease absorption. Thus, available transport mechanisms may become saturated and unable to absorb the excess dose of the vitamin, mineral, or other nutrient. Additionally, a drawback to vitamin or mineral delivery via a conventional tablet or capsule is that differences in luminal pH along the gastrointestinal tract lining, surface area per luminal volume, blood perfusion, presence of bile and mucus, and the nature of epithelial membranes may prevent or alter efficient absorption, activation, and the like of a nutrient, thereby decreasing its bioavailability and subsequent usage by the human body.
To compensate for first pass metabolism effects, some previous efforts have been directed to enteric coated tablet or capsule dosage forms which pass through the stomach unaltered to disintegrate in the lower intestines. However, aside from a delayed biophysiological response as gastric emptying becomes rate-limiting, gastric irritability, and potential allergic reactions from the ingestion of such coating materials occurs, and these enteric coated delayed release dosage forms dissolve and are absorbed within a narrow time frame. As a result, the body typically excretes the non-absorbed vitamins or minerals.
Additional previous attempts in addressing the challenge of bypassing first pass metabolism have been directed to continuous or gradual release dosage forms. U.S. Pat. No. 4,882,167, to Jang, discloses dry direct compressed products for controlled release of actives including vitamins or minerals. However, there still remains the challenge of a composition having ultra-low dosage amounts of vitamins or minerals, dosing flexibility, or alternatively systems, compositions, or methods for individualized responsive dosing based on at least one desired biological response such as increased sleep quality or treatment of a sleep disorder.
WO 99/17753 (to Awamura et al.) discloses rapidly dissolving films for delivery of drugs to be adsorbed in the digestive tract. U.S. Pat. No. 6,596,298, to Leung, discloses consumable oral care films which may optionally contain active amounts of pharmaceutical drugs. However, there still remains the challenge of utilizing vitamins or minerals, and more specifically, ultra-low dosage amounts of nutrients which would operate to provide flexibility for individualized dosing, especially in the promotion, enhancement or improvement in sleep initiation, maintenance, and/or quality. Moreover, these products or processes do not provide a system or selection for varying the type or level of dosage depending on a biological response desired, such as a focus upon sleep.
Therefore, there is presently a need for an efficient process for producing a nutrient dosage and delivery system that is capable of individualized biological response dosing (i.e., dosing based upon empirical analysis and adjustment in response to a desired biological outcome such as enhanced sleep quality and the like), which is available in a suitable dosage form, and preferably is efficiently absorbed and made bioavailable to animal or human tissue. Additionally, there is presently a need for a treatment method for managing finely tuned biological needs and responses which utilizes micro- and nano-quantities of the actives in ultra-low dosage amounts, substantially avoids first pass metabolism, and allows for varied dosage/dosing regimens within each dosing period (e.g., 24 hours, 6 hours, 1 hour). Furthermore, there exists a present need for an ultra-low dose nutraceutical having micro- and nano-quantities of actives that substantially avoids first pass metabolism, and which increases n3 stage non-REM sleep and glymphatic system activation to allow for clearing of neuronal metabolites from the CSF and interstitial brain fluids.